This new RO1 proposal explores novel mechanisms of cardioprotection involving micro-axial flow pumps (TV- Pumps) as a platform to reduce myocardial damage and heart failure (HF) after an acute myocardial infarction (AMI). Prior attempts to limit reperfusion injury have failed in part due to the mandate for rapid coronary reperfusion, thereby limiting time for any beneficial impact of a therapeutic agent. We recently reported that mechanically unloading the left ventricle (LV) and delaying reperfusion (Primary Unloading) reduces infarct size and increases expression of the cardioprotective cytokine stromal derived factor 1 alpha (SDF1a). We will now explore new mechanisms regulating the cardioprotective effect of Primary Unloading and further test the durable impact of acutely reducing infarct size using this approach. The PI is an interventional cardiologist and advanced heart failure specialist who studies molecular mechanisms of cardiac remodeling and the hemodynamic effects of circulatory support pumps. The current proposal integrates expertise in coronary and ventricular physiology, mechanical circulatory support, molecular biology, and interventional cardiology to the field of myocardial reperfusion injury, for which no specific therapy currently exists. We will test the novel hypothesis that activating a TV-Pump and delaying coronary reperfusion (Primary Unloading) limits myocardial damage through a two-component mechanism involving: 1) reduced LV wall stress, myocardial oxygen demand, and increased collateral blood flow thereby reducing ischemic injury prior to reperfusion and 2) activation of a cardioprotective signaling program that requires intact SDF1a activity and further that these beneficial mechanisms will improve long term outcomes. Exciting new preliminary data shows that Primary Unloading for 30 minutes reduces infarct size by 50% and promotes a graded increase in collateral blood flow that reduces ischemic injury before reperfusion through the infarct related artery. Using intracoronary delivery of pharmacologic inhibitors and recombinant peptides during LV unloading, we further identified that Primary Unloading limits SDF1a degradation and sequestration, thereby promoting SDF1a activity. These pioneering approaches address major knowledge gaps by studying the effect of Primary Unloading on coronary blood flow and wave energetics and further overcome critical barriers associated with cardioprotection in AMI. To test our central hypothesis we will employ highly translational studies in large animal models to determine the physiologic (SA1) and molecular signaling (SA2) mechanisms underlying the cardioprotective effect of Primary Unloading and (SA3) to test the therapeutic utility of Primary Unloading to reduce late-term cardiac remodeling after AMI. This proposal has tremendous potential to impact our understanding of coronary and ventricular physiology, acute mechanical circulatory support, cardioprotection, and cardiac remodeling with important implications for AMI patients at risk of ischemic HF.